title: Expression of DIAPH1 is up-regulated in colorectal cancer and its down-regulation strongly reduces the metastatic capacity of colon carcinoma cells.
abstract: In most cases, metastatic colorectal cancer is not curable, thus new approaches are necessary to identify novel targets for colorectal cancer therapy. Actin-binding-proteins (ABPs) directly regulate motility of metastasising tumor cells, and for cortactin an association with colon cancer metastasis has been already shown. However, as its depletion only incompletely inhibits metastasis, additional, more suitable cellular targets have to be identified. Here we analyzed expression of the ABPs, DIAPH1, VASP, N-WASP, and fascin in comparison with cortactin and found that, besides cortactin, DIAPH1 was expressed with the highest frequency (63%) in colorectal cancer. As well as cortactin, DIAPH1 was not detectable in normal colon tissue and expression of both proteins was positively correlated with metastasis of colorectal cancer. To analyse the mechanistic role of DIAPH1 for metastasis of colon carcinoma cells in comparison with cortactin, expression of the proteins was stably down-regulated in the human colon carcinoma cell lines HT-29, HROC-24 and HCT-116. Analysis of metastasis of colon carcinoma cells in SCID mice revealed that depletion of DIAPH1 reduced metastasis 60-fold and depletion of cortactin 16-fold as compared with control cells. Most likely the stronger effect of DIAPH1 depletion on colon cancer metastasis is due to the fact that in vitro knock down of DIAPH1 impaired all steps of metastasis; adhesion, invasion and migration while down-regulation of cortactin only reduced adhesion and invasion. This very strong reducing effect of DIAPH1 depletion on colon carcinoma cell metastasis makes the protein a promising therapeutic target for individualized colorectal cancer therapy.
authors.affiliation: Department of General Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Yuan-Na
authors.initials: YN
authors.lastname: Lin
authors.forename: Jakob R
authors.initials: JR
authors.lastname: Izbicki
authors.forename: Alexandra
authors.initials: A
authors.lastname: König
authors.forename: Jens K
authors.initials: JK
authors.lastname: Habermann
authors.forename: Christine
authors.initials: C
authors.lastname: Blechner
authors.forename: Tobias
authors.initials: T
authors.lastname: Lange
authors.forename: Udo
authors.initials: U
authors.lastname: Schumacher
authors.forename: Sabine
authors.initials: S
authors.lastname: Windhorst
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D002277:Carcinoma / Q000235:genetics / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D003106:Colon / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051356:Cortactin / Q000235:genetics; D015536:Down-Regulation; D005260:Female; D000080865:Formins; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008840:Microfilament Proteins / Q000235:genetics; D009362:Neoplasm Metastasis; D015854:Up-Regulation / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051356:Cortactin; C108962:DIAPH1 protein, human; D000080865:Formins; D008840:Microfilament Proteins
keywords: actin; adhesion; colon cancer; formins; invasion; metastasis; migration